WO2012046193A1

WO2012046193A1 - New salt of a pyrimidin derivative

Info

Publication number: WO2012046193A1
Application number: PCT/IB2011/054369
Authority: WO
Inventors: Juan Pablo SENOSIAIN PELÁEZ; Héctor SENOSIAIN ARROYO; Manuel Francisco Lara Ochoa
Original assignee: Laboratorios Senosiain S.A. De C.V.
Priority date: 2010-10-06
Filing date: 2011-10-04
Publication date: 2012-04-12
Also published as: US8846708B2; CA2813388A1; ES2409805B1; ES2409805R1; BR112013008330A2; US20130210848A1; ES2409805A2; MX2010011006A

Abstract

The invention relates to a salt of a pyrimidin derivative of the acid (3R,5S,6E)-7-[4-(4-fluorophenyl)-2-(N-methylmethanesulfonamide)-6-(propan-2-yl)pyrimidin-5-yl]-3,5-dihydroxyhept-6-enoic, to a method for preparing same and to the use thereof in formulating pharmaceutical formulations.

Description

NEW SALT OF A PYRIMIDINE DERIVATIVE

FIELD OF THE INVENTION

The present invention comprises a salt of a pyrimidic derivative, more particularly of an acid salt (3R, 5S, 6E) -7- [4- (4-fluorophenyl) -2- (N-methylmethanesulfonamido) -6- (propane- 2-yl) pyrimidin-5-yl] -3, 5- dihydroxyhepta-6-oenic, as well as a process for its preparation and the use of said salt for the preparation of pharmaceutical formulations.

BACKGROUND OF THE INVENTION

Cardiovascular diseases and dyslipidemia are currently recurrent conditions for which there are different medications including statins, fibrates and combinations thereof.

Rosuvastatin, pyrimidine derivative, is an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which catalyzes the conversion of HMG-CoA to mevalonate, initial limiting step of cholesterol biosynthesis. It has a relative hydrophilic capacity. Its metabolism does not depend on Cytochrome P450 (CYP), presenting fewer pharmaceutical interactions than atorvastatin and simvastatin. Rosuvastatin is mainly used as calcium salt (formula I). This salt has an absolute bioavailability of approximately 20%, binds to proteins in 88%, reaching a maximum peak between 3 and 5 hours. It is excreted mainly by feces (90%) and urine (10%), with a half-life of 19 hours.

Formula I

Rosuvastatin is slightly soluble in water, it is not very stable in extreme environmental conditions, it is a compound with acidic characteristics, therefore, it is mainly associated with compounds of basic characteristics such as metal salts of calcium, zinc, strontium, sodium, magnesium, lithium, among others. From the different publications on rosuvastatin it is observed that there are problems during the synthesis process for obtaining rosuvastatin salts and during the purification and crystallization processes. Therefore, it is visualized that the problem of having stable salts that can be used in the preparation of stable compositions could not be solved physically.

US5260440, (USRE37314-Shionogi) describes the synthesis of acid (3R, 5S, 6E) -7- [4- (4-fluorophenyl) -2- (JV-methylmethanesulfonamido) -6- (propan-2-yl) pyrimidin-5-yl] - 3, 5-dihydroxyhept-6-enoic, commonly called rosuvastatin. This patent describes a complex process for obtaining rosuvastatin with diastereoisomeric impurities. In contrast, a new rosuvastatin salt with better stability and solubility properties is obtained without diastereoisoomeric impurities.

International application WO2000 / 042024, describes processes for obtaining amorphous rosuvastatin, where the impurities of rosuvastatin are obtained in a smaller amount, compared to the process disclosed in US 40. The process of application WO2000 / 042024, unlike the application The present invention is characterized by presenting a method of purification of rosuvastatin to obtain calcium rosuvastine and rosuvastatin is not present as an amino acid salt, as is the object of the present invention.

Document W02001 / 060804-ASTRAZENECA (Mexican Application PA / a / 2002/000781, Patent US6841554) describes the preparation of crystalline salts of rosuvastatin in order to solve the technical problems of the process disclosed in US5260440. These crystalline salts are more easily purified compared to an amorphous form, are more physically stable and are more resistant to oxidative degradation. This document mentions the development of rosuvastatin ammonium, methylammonium, ethylammonium, diethylammonium, tris (hydroxymethyl) methylammonium, benzyl ammonium, 4-methoxybenzylammonium, lithium or magnesium salt salts. This document refers to stable salts where the anion is a metal or an ammonium compound, unlike the present invention which refers to stable salts with amino acid.

WO2004 / 014872 of ASTRA (Sol. Mexicana PA / a / 2005/001582, US7511140) describes the preparation of a calcium rosuvastatin salt that demonstrates an efficiency in its synthesis process, in particular in the filtration stage, which It is characterized in that a calcium chloride salt is mixed with a solution of a water-soluble rosuvastatin sodium salt. This is an improvement in the process of obtaining rosuvastatin calcium salt, however, the salt described does not correspond to the salts of the present invention.

Patent document US7582759 of TEVA (Mexican Application MX / a / 2007/037979, WO2006091770, EP1737829), describes the preparation of rosuvastatin intermediates and salts thereof, includes the use of an alcohol of the methanol type with an organic solvent and a source of hydride ions. A pure enantiomeric salt of rosuvastatin is obtained without including salts formed with amino acids.

Document MX / a / 2007/009281 -Lifecycle Pharma A / S (WO06084474, US2008131503), presents an oral composition comprising a mixture that combines a fenofibrate and an HMG-CoA reductase compound that is presented in separate entities in a single dose . HMG-CoA reductase is a statin selected from the group of atorvastatin, lovastatin, pravastatin, simvastatin, rosuvastatin, fluvastatin and pitavastatin being the preferred atorvastatin. Unlike this formulation, the present invention offers a stable salt and with improved solubility of rosuvastatin, as well as its method of synthesis and obtaining it.

WO06126035-Richter Gedeon Vegyészeti Gyár Rt. HU (EP1902036B), relates to a process for preparing Rosuvastatin calcium starting from (6- {(E) -2 [4- (4- fluorophenyl) -6-isopropyl-2- (methanesulfonyl-methyl-amino) pyrimidin-5-yl] -vinyl} - (4R, 6S) -2,2-dimethyl- [1,3] dioxane-4-yl) acetic acid, which may preferably be presented as salt of diethanolamine, L-lysine or magnesium. These salts are reacted with chloride of calcium in the presence of a base to remove the acetonide group and obtain calcium rosuvastatin as the final product. Unlike this formulation, the present invention offers a process for obtaining a lysine rosuvastatin and non-rosuvastatin salt without starting from an intermediate and in a shorter time than the synthesis process described in WO06126035.

WO07089745 - Signature R&D Holdings Lie (US7589233), refers to a method for improving at least one therapeutic property of an active ingredient, by combining an amino acid with an active ingredient. The compositions may preferably be the combination of an L-Threonine derivative with an active ingredient that is selected from different therapeutic groups where one of them may be rosuvastatin, resulting in the physical combination of threonine and rosuvastatin. The present invention relates to the synthesis of a lysine rosuvastatin salt where the salt thus obtained has better solubility and physicochemical stability properties, and is useful for preparing a medicament.

WO2006 / 136407 Lek Pharm. (US2009111839, EP1912952A) describes a process of preparing a pure form of amorphous rosuvastatin with a purity ranging from 99.5% to 99.9%, where the process is carried out by hydrolysis of C1-C5 of the rosuvastatin alkyl ester, preferably ter-butyl ester of rosuvastatin with a nitrogen base such as guanidine, amidine, amines and quaternary ammonium hydroxides, in the presence of water or an aprotic solvent.

Rosuvastatin base and amorphous rosuvastatin salts are very unstable and poorly soluble in aqueous solutions, therefore, it is an objective of the present invention to present a rosuvastatin salt with better solubility and stability properties. There are different rosuvastatin salts as well as new purification processes for these salts. Existing rosuvastatin salts are basic and mineral salts such as magnesium, lithium, aluminum, zinc, strontium salts, among others, and can be amorphous or non-amorphous salts. Its preparation methods are given by complex processes with organic solvents, filtration, drying, recrystallization processes and others that increase the operating time as well as its cost in the elaboration.

The present invention makes available a new rosuvastatin salt, which is more stable and more soluble than the rosuvastatin salts available for the preparation of pharmaceutical compositions.

JUSTIFICATION OF THE INVENTION For the production of rosuvastatin salts with magnesium, lithium, aluminum, zinc, strontium and calcium there are different processes that to date still have the problem of generating diastereoisomeric impurities, in addition to presenting problems of solubility during the preparation of pharmaceutical forms. Therefore, a process is necessary to obtain a rosuvastatin salt with a smaller amount of by-products, where the salt is stable to prepare a physico-chemically stable pharmaceutical composition and useful for the treatment of cardiovascular diseases.

The present invention provides an amino acid rosuvastatin salt with improved aqueous solubility and more physicochemical stability, which provides greater absolute bioavailability and a pharmacokinetic improvement when preparing a pharmaceutical composition.

However, obtaining this salt is not possible by simply associating rosuvastatin with any amino acid since the particular conditions must be created during the production process, such as selecting the appropriate raw materials, atmosphere, temperature, humidity, pH; An example of this is that, in contrast to what you might expect, salt production is not possible with arginine.

The present invention comprises a salt of rosuvastatin with an amino acid that can be lysine or histidine, in a non-limiting manner.

The rosuvastatin salt of this invention can be obtained with good yield and good purity, such that this salt is especially suitable for the preparation of pharmaceutical formulations.

The lysine rosuvastatin salt of the present invention offers better fluidity compared to a calcium salt. This property offers you better conditions to prepare a pharmaceutical composition.

In the solubility study, the rosuvastine-lysine of the present invention has a greater and better aqueous solubility, being 218mg / mL against 5.3mg / mL of calcium rosuvastatin, which represents an increased solubility of just over 40%. This property allows it to be more bioavailable in the body when presented in pharmaceutical compositions.

BRIEF DESCRIPTION OF THE DRAWINGS

The figures illustrate the result of the characterization of the R-Lysine salt.

Figure 1. Differential thermal spectrum (DSC)

Figure 2. Thermogravimetric analysis spectrum

(TGA). Figure 3a. X-ray diffractogram of calcium rosuvastatin.

Figure 3b X-ray diffractogram of rosuvastatin lysine.

Figure 3c X-ray diffractogram of rosuvastatin-lysine monohydrate.

Figure 4. X-ray diffractogram of rosuvastatin calcium, rosuvastatin lysine and lysine monohydrate at 30 days and 40 ° C.

Figure 5. X-ray diffractogram of rosuvastatin-lysine at zero time and rosuvastatin-lysine after being subjected to a stability study under conditions of 40 ° C for 30 days. DETAILED DESCRIPTION OF THE INVENTION

The present invention consists in a process of obtaining a stable rosuvastatin salt, with high purity, with an improved solubility that allows to manufacture a pharmaceutical composition with a stability in the process and the shelf that allows it to retain its therapeutic properties as long as possible. In addition to this, with the increase in solubility in aqueous media, bioavailability is facilitated in the organism once presented in pharmaceutical form. SYNTHESIS METHOD OF THE NEW SALT OF ROSUVASTATINA

A synthesis scheme of the rosuvastatin-amino acid salt of the present invention is illustrated below. By way of example, the scheme shows the obtaining of the rosuvastatin lysine salt of Formula II.

Formula II

Diagram of the synthesis process of rosuvastatin salt - amino acid

In the present invention of obtaining a rosuvastatin-amino acid salt, it is based on the calcium rosuvastatin salt (Formula I), this salt is subjected to a process of dissociation in the presence of a solution of ethyl acetate / water and hydrochloric acid.

The resulting acidic rosuvastatin is mixed with an aqueous solution containing the amino acid selected for the formation of the new salt, in the presence of a methanol / ethyl acetate solution.

To stabilize the combination, the reaction medium is preserved with constant agitation.

Finally, a rosuvatatin-amino acid salt is obtained which is achieved through a non-covalent bond, this new salt is stable and has an improved aqueous solubility compared to the calcium rosuvastatin salt.

The rosuvastatin-lysine salt (Formula II) obtained with the process of the present invention was carried out identification and stability tests with which it is shown that the salt obtained is useful in the preparation of a pharmaceutical composition.

IDENTITY ANALYSIS

DSC Differential Thermal Analysis and Thermal Analysis of

TGA-DTG gravimetry (Figures 1 and 2). With these analyzes the weight loss of the analyzed sample was determined. The result reflects a 2.9% weight loss that begins in

30 ° C and ends at 115 ° C. This corresponds to the loss of one mole of water, as well as another weight loss that begins in 190 ° C and ends at 290 ° C, which corresponds to the decomposition of Lysine.

For an X-ray powder diffraction analysis

(Figures 3a-3c), a comparative test was performed between a sample of calcium rosuvastatin (figure 3a), rosuvastatin lysine (figure 3b) and lysine monohydrate (figure 3c), where the lysine monohydrate reading shows us that the new salt does not It is a single sum of rosuvastatin and lysine (it would give us a sum of spikes). This demonstrates the differentiation of the new rosuvastatin lysine salt.

With these analyzes, the new rosuvastatin lysine salt was identified in detail and the stability test was continued.

STABILITY TESTS

An X-ray diffraction test of a sample of rosuvastatin lysine (R-Lys), calcium rosuvastatin (R-Ca) and lysine monohydrate (L-Lys.H20) was performed to check its stability (Figure 4). The samples were subjected to conditions of 40 ° C for a period of 30 days. The results obtained allow us to observe a peak constant in the reading for the rosuvastatin-lysine sample, which demonstrates that this salt remains physically stable. The X-ray spectrum of Figure 4 for salts Rosuvastatin calcium (R-Ca) and rosuvastatin-lysine (R-Lys) gives readings on a scale ranging from 0 to 8000 in intensity, however for L-lysine monohydrate (L-Lys-H20) the X-ray reading It gives very high peaks whose values leave the scale in thousands, for this reason an enlarged scale was placed on the vertical axis of the right side.

Additionally, the new salt of the present invention was subjected to an accelerated stability test at 40 ° C for 30 days, then an X-ray diffraction test was performed on this sample and compared with the X-ray diffraction analysis performed to the sample at the start time. The results are shown in Figure 5. The sample submitted to the stability study at 40 ° C for 30 days is represented as R-Lys-EST, and the salt sample at zero time is represented as R-Lys. It can be verified that the new salt preserves its bond and its integrity by exhibiting spectra with the same characteristic peaks, which shows that rosuvastatin lysine salt is stable and can be used for the preparation of a pharmaceutical composition.

COMPARATIVE SOLUBILITY TEST

Additionally, a comparative solubility test was performed between rosuvastatin calcium and rosuvastatin lysine. The following table shows the results obtained from the comparative solubility tests of calcium salt and lysine salt, using different solvents.

From the table above, a better solubility and fluidity for Rosuvastatin-Lysine salt is observed.

Rosuvastatin-lysine has a better solubility and in a preferred embodiment is useful in the preparation of pharmaceutical compositions that meet specifications of physicochemical stability, dissolution and bioavailability.

Here are some exemplary formulation without being limiting FORMULATION EXAMPLE 1

Rosuvastatin 4.5mg powder, administered as rosuvastatin lysine salt, lactose (124.5mg), microscrystalline cellulose (60mg) and magnesium stearate (lmg) are mixed, passed through a No. 40 mesh and filled into a capsule .

FORMULATION EXAMPLE 2

Rosuvastatin 4.5mg powder, administered as rosuvastatin lysine salt, lactose (119.5mg), microscrystalline cellulose (75mg) and magnesium stearate (lmg) are mixed and compressed with a tabletting machine, carried at a weight of 200mg. The tablet is optionally coated. The formulation examples are not limiting to be used only with rosuvastatin lysine salt, but with other amino acid salts such as histidine.

In addition to the advantages presented by the use of rosuvastatin lysine salt, it is possible to prepare pharmaceutical compositions using other substances, which can be selected from ascorbic acid, lactic acid, citric acid, among others.

The invention has been described sufficiently that a person with average knowledge in the field can reproduce and obtain the results mentioned in the present description However, any person with experience in the field of the art that is in charge of the present invention may be able to make modifications not described in the present application. Therefore, if the matter claimed in the following claims is required for the application of these modifications in a given method, said method must be within the scope of the present invention.

Claims

1. Amino acid salts of (3R, 5S, 6E) -7- [4- (4- fluorophenyl) -2- (N-methylmethanesulfonamido) -6- (propan-2- yl) pyrimidin-5-yl] -3 , 5-dihydroxyhepta-6-oenic.

2. Amino acid salt of (3R, 5S, 6E) -7- [4- (4-fluorophenyl) -2- (N-methylmethanesulfonamido) -6- (propan-2-yl) pyrimidin-5-yl] -3 , 5-dihydroxyhepta-6-oenic, wherein the amino acid is selected from lysine or histidine.

3. Pharmaceutical composition characterized in that it comprises a rosuvastatin-lysine salt or a rosin salt of tatin-histidine in combination with a pharmaceutically acceptable carrier.

4. The use of amino acid salts of (3R, 5S, 6E) -7- [4- (4- fluorophenyl) -2- (N-methylmethanesulfonamido) -6- (propan-2- yl) pyrimidin-5-yl ] -3,5-dihydroxyhepta-6-oenic, for the preparation of pharmaceutical compositions.

5. The use of an amino acid salt of (3R, 5S, 6E) -7- [4- (4- fluorophenyl) -2- (N-methylmethanesulfonamido) -6- (propan-2-yl) pyrimidin-5- il] -3,5-dihydroxyhepta-6-oenic for the preparation of pharmaceutical compositions, wherein the amino acid is selected from lysine or histidine.

6. The use of compound (3R, 5S, 6E) -7- [4- (4-fluorophenyl) -2- (N-methylmethanesulfonamido) -6- (propan-2-yl) pyrimidin-5-yl] -3 , 5-dihydroxyhepta-6-oenic, in accordance with claim 5 or 6 for the preparation of pharmaceutical compositions in the form of tablets or capsules.

7. The use of the compound of claim 1 for the preparation of medicaments for the prevention or treatment of cardiovascular diseases.

8. A process to synthesize a rosuvastatin-amino acid salt, characterized in that it comprises the steps of:

a) Subject the calcium rosuvastatin salt to a dissociation process; Y

b) The acid rosuvastatin resulting from the previous step is mixed with an aqueous solution containing the amino acid selected for salt formation, in the presence of a methanol / ethyl acetate solution.